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Introduction: Hemostasis depends on the delicate balance between coagulants and anticoagulants. Higher levels of circulating coagulants have been associated with higher risk of cerebral infarctions and dementia. In contrast, higher levels of circulating protein C, an endogenous anticoagulant, have been associated with lower risk of cerebral infarctions, and the association between protein C levels and the risk of dementia is unknown. The goal of this study was to evaluate the association of circulating protein C levels in midlife and late life with incident dementia. Methods: Circulating protein C levels were measured using blood samples collected at the midlife baseline (1987–1989) and the late-life baseline (2011–2013) among 14,462 and 3,614 participants, respectively, in the Atherosclerosis Risk in Communities study. Protein C levels were measured using enzyme-linked immunosorbent assay at midlife and a modified aptamer-based assay at late life. Participants were followed up to 2013 from midlife and up to 2017 from late life. Incident dementia was ascertained during the follow-up periods using in-person cognitive and functional assessment, informant interviews, and International Classification of Diseases codes at hospitalization discharge and on death certificates. Cause-specific Cox regression models were used to evaluate the association between quintiles of circulating protein C and incident dementia. Results: From midlife (mean age of 54), 1,389 incident dementia events were observed over a median follow-up of 23 years. From late life (mean age of 75), 353 incident dementia events were observed over a median follow-up of 4.9 years. At both midlife and late life, circulating protein C had an inverse association with incident dementia after adjusting for demographic, vascular, and hemostatic risk factors, incident stroke as time-dependent covariate, and incorporating stabilized weights based on propensity scores (quintile 5 vs. quintile 1 as the reference, midlife hazard ratio 0.80, 95% confidence interval 0.66–0.96, p value for trend 0.04; late-life hazard ratio 0.84, 95% confidence interval: 0.55–1.28, p value for trend 0.04). Discussion/Conclusion: Circulating protein C has an inverse association with incident dementia independent of established risk factors, including stroke. Our results suggest studying anticoagulants in addition to coagulants can increase our understanding on the relationship between hemostasis and dementia.

Introduction Clinic-based study samples, including the Alzheimer's Disease Neuroimaging Initiative (ADNI), offer rich data, but findings may not generalize to community-based settings. We compared associations in ADNI to those in the Atherosclerosis Risk in Communities (ARIC) study to assess generalizability across the two settings. Methods We estimated cohort-specific associations among risk factors, cognitive test scores, and neuroimaging outcomes to identify and quantify the extent of significant and substantively meaningful differences in associations between cohorts. We explored whether using more homogenous samples improved comparability in effect estimates. Results The proportion of associations that differed significantly between cohorts ranged from 27% to 34% across sample subsets. Many differences were substantively meaningful (e.g., odds ratios [OR] for apolipoprotein E e4 on amyloid positivity in ARIC: OR = 2.8, in ADNI: OR = 8.6). Discussion A higher proportion of associations differed significantly and substantively than would be expected by chance. Findings in clinical samples should be confirmed in more representative samples.

Background We examined the relationship of midlife cardiovascular health (CVH) with late-life robustness among men and women and the impact of survivorship bias on sex differences in robustness. Methods Prospective analysis of 15 744 participants aged 45–64 (visit 1 median age: 54 years, 55% female, 27% Black) in 1987–1989 from the population-based Atherosclerosis Risk in Communities Study. CVH was operationalized according to the Life’s Simple 7 (LS7) metric of health behaviors (smoking, weight, physical activity, diet, cholesterol, blood pressure, and glucose); each behavior was scored as ideal (2 points), intermediate (1 point), or poor (0 points) and summed. Late-life robust/prefrail/frailty was defined at visit 5 (2011–2013). Multinomial regression estimated relative prevalence ratios (RPRs) of late-life robustness/prefrailty/frailty/death across overall midlife LS7 score and components, for the full visit 1 sample. Separate analyses considered visit 5 survivors-only. Results For each 1-unit greater midlife LS7 score, participants had a 37% higher relative prevalence of being robust versus frail (overall RPR = 1.37 [95% confidence interval {CI}: 1.30–1.44]; women = 1.45 [1.36–1.54]; men = 1.24 [1.13–1.36]). Among the full visit 1 sample, women had a similar 1-level higher robustness category prevalence (RPR = 1.35 [95% CI: 1.32–1.39]) than men (RPR = 1.31 [95% CI: 1.27–1.35]) for every 1-unit higher midlife LS7 score. Among survivors, men were more likely to be robust than women at lower LS7 levels; differences were attenuated and not statistically different at higher midlife LS7 levels. Conclusions Midlife CVH is positively associated with robustness in late life among men and women. Accounting for mortality in part explains documented sex differences in robustness across all levels of LS7.

[This corrects the article DOI: 10.1371/journal.pmed.1003012.].

Background Sudden cardiac death (SCD) is associated with severe coronary heart disease in the great majority of cases. Whether carotid intima‐media thickness (C‐IMT), a known surrogate marker of subclinical atherosclerosis, is associated with risk of SCD in a general population remains unknown. The objective of this study was to investigate the association between C‐IMT and risk of SCD. Methods and Results We examined a total of 20 862 participants: 15 307 participants of the ARIC (Atherosclerosis Risk in Communities) study and 5555 participants of the CHS (Cardiovascular Health Study). C‐IMT and common carotid artery intima‐media thickness was measured at baseline by ultrasound. Presence of plaque was judged by trained readers. Over a median of 23.5 years of follow‐up, 569 participants had SCD (1.81 cases per 1000 person‐years) in the ARIC study. Mean C‐IMT and common carotid artery intima‐media thickness were associated with risk of SCD after adjustment for traditional risk factors and time‐varying adjustors: hazard ratios (HRs) with 95% CIs for fourth versus first quartile were 1.64 (1.15–2.63) and 1.49 (1.05–2.11), respectively. In CHS, 302 participants developed SCD (4.64 cases per 1000 person‐years) over 13.1 years. Maximum C‐IMT was associated with risk of SCD after adjustment: HR (95% CI) for fourth versus first quartile was 1.75 (1.22–2.51). Presence of plaque was associated with 35% increased risk of SCD: HR (95% CI) of 1.37 (1.13–1.67) in the ARIC study and 1.32 (1.04–1.68) in CHS. Conclusions C‐IMT was associated with risk of SCD in 2 biracial community‐based cohorts. C‐IMT may be used as a marker of SCD risk and potentially to initiate early therapeutic interventions to mitigate the risk.

Introduction: Cerebrovascular small vessel disease, seen on brain imaging as lacunes and white matter hyperintensities (WMH), is a substrate for dementia in older adults. Diffusion tensor imaging (DTI) is thought to provide early signs of loss of white matter (WM) integrity due to microvascular disease and predicts WM hyperintensity volume. Retinal fundus photography provides surrogate measures of cerebral microvasculature. No studies have quantified the long-term association between retinal signs and DTI measures. Hypothesis: Microvascular retinal signs measured in midlife are associated with small vessel disease measured on brain magnetic resonance imaging (MRI) 18 years later, including reduced WM microstructural integrity (lower fractional anisotrophy [FA] and greater mean diffusivity [MD] by DTI), greater WM hyperintensity volume and greater lacune prevalence. Methods: In a biracial prospective cohort study, retinal signs were measured using fundus photography (1993-1995) with 3-T magnetic resonance imaging conducted in 2011-13. Multivariable-adjusted linear regression was used to quantify the relationships of retinal signs with WM measures. Prevalence of lacunar infarcts by retinal sign status was estimated using log binomial regression. Analyses were adjusted for age [linear and quadratic terms], education, sex, race, intracranial volume, body mass index, smoking, diabetes, hypertension, and ≥1 APOE ε4 alleles. Results: In 1829 men and women (60% [N=1100] female, 27% [N=489] black race, aged 50-72 years when retinal signs were measured), a binary measure comprised of two retinal signs suggestive of arteriolar damage due to hypertension (focal arteriolar narrowing and/or arteriovenous nicking) was associated with worse (lower) FA (standardized β=-0.19, 95% confidence interval [CI]=-0.35, -0.02), worse (higher) MD (β=0.15, 95% CI=0.00, 0.30), greater WM hyperintensity volume (β=0.15, 95% CI=0.01, 0.30), and greater prevalence of lacunes (prevalence ratio=1.33, 95% CI: 0.99, 1.80). Generalized arteriolar narrowing, measured as the central retinal arteriolar equivalent (CRAE, narrowest quartile vs. widest three quartiles) was associated with worse FA (β=-0.13, 95% CI=-0.24, -0.01) and worse MD (β=0.12, 95% CI=0.01, 0.23). Results did not differ by sex, race, hypertension status or APOE ε4 genotype. No associations were found for retinopathy, but only 56 participants had retinopathy. Conclusions: Consistent with prior work, and as expected based on a common underlying pathology, retinal signs predicted WM disease and lacunar infarcts 18 years later. Novel to this study, we found that retinal signs related to arteriolar damage also predicted loss of white matter microvascular integrity measured using DTI.

Objective To review the literature systematically and perform meta-analyses to address these questions: 1) Is there evidence that self-measured blood pressure (BP) without other augmentation is superior to office-based measurement of BP for achieving better BP control or for preventing adverse clinical outcomes that are related to elevated BP? 2) What is the optimal target for BP lowering during antihypertensive therapy in adults? 3) In adults with hypertension, how do various antihypertensive drug classes differ in their benefits and harms compared with each other as first-line therapy? Methods Electronic literature searches were performed by Doctor Evidence, a global medical evidence software and services company, across PubMed and EMBASE from 1966 to 2015 using key words and relevant subject headings for randomized controlled trials that met eligibility criteria defined for each question. We performed analyses using traditional frequentist statistical and Bayesian approaches, including random-effects Bayesian network meta-analyses. Results Our results suggest that: 1) There is a modest but significant improvement in systolic BP in randomized controlled trials of self-measured BP versus usual care at 6 but not 12 months, and for selected patients and their providers self-measured BP may be a helpful adjunct to routine office care. 2) systolic BP lowering to a target of

Introduction We tested the hypothesis that poor sense of smell is associated with lower cognitive function and higher mild cognitive impairment (MCI) prevalence. Methods Olfaction, measured by the Sniffin' Sticks test, was categorized as olfactory impairment (OI) (score ≤6) or no OI (score >6). MCI was adjudicated based on review of a neuropsychological examination. Linear regression estimated the mean difference in cognitive factor scores, and log-binomial regression quantified MCI prevalence among participants with versus without OI. Results Participants with OI had lower mean factor scores (memory: −0.27 standard deviation [SD], 95% confidence interval [CI]: −0.35 to −0.19; language: −0.24 SD, 95% CI: −0.30 to −0.17; executive function/processing speed: −0.09 SD, 95% CI: −0.12 to −0.06; and general cognitive performance: −0.25 SD, 95% CI: −0.30 to −0.20). OI was also associated with MCI (n = 204; prevalence ratio = 1.56, 95% CI: 1.37, 1.78). Discussion An impaired sense of smell may serve as a readily accessible early marker of neurodegeneration and improve upon the prevailing delayed diagnoses and underascertainment of MCI/dementia.

OBJECTIVES: MRI has become an indispensable tool for brain volumetric studies, with the hippocampus an important region of interest. Automation of the MRI segmentation process has helped advance the field by facilitating the volumetric analysis of larger cohorts and more studies. FreeSurfer has emerged as the de facto standard tool for these analyses, but studies validating its output are all based on older versions. To characterize FreeSurfer’s validity, we compare several versions of FreeSurfer software with traditional hand-tracing. EXPERIMENTAL DESIGN: Using MRI images of 262 males and 402 females aged 38 to 84, we directly compare estimates of hippocampal volume from multiple versions of FreeSurfer, its hippocampal subfield routines, and our manual tracing protocol. We then use those estimates to assess asymmetry and atrophy, comparing performance of different estimators with each other and with brain atrophy measures. PRINCIPAL OBSERVATIONS: FreeSurfer consistently reports larger volumes than manual tracing. This difference is smaller in larger hippocampi or older people, with these biases weaker in version 6.0.0 than prior versions. All methods tested agree qualitatively on rightward asymmetry and increasing atrophy in older people. CONCLUSIONS: FreeSurfer saves time and money, and approximates the same atrophy measures as manual tracing, but it introduces biases that could require statistical adjustments in some studies.

Poor lung function has been linked with adverse neurocognitive outcomes including dementia, but evidence from well-designed prospective studies is limited. We therefore examined the association between lung function, as measured by forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC), and dementia risk in 12,688 participants of the ARIC study, a prospective study of adults aged 46-70 years (at index visit, mean age =57y, 45% male, 76% White) from four US communities. Lung function was assessed in 1991-1992 (index visit, 76% normal, 16% obstructive, and 8% restrictive lung function), and dementia was ascertained through 2019 via in-person assessments, telephone interviews, and medical record surveillance, with adjudication of dementia with all in-person exams. A total of 2452 developed dementia over 30 years of follow-up. We used Cox proportional hazards model to estimate hazard ratio (HR) and 95% confidence intervals (CI), adjusting for potential confounders (socio-demographics, behavioral factors, cardiovascular risk factors, APOE ε4). Higher FEV1 and FVC were associated with reduced dementia risk [(HR: 0.86, 95%CI: 0.78-0.98, per 1L increase in FEV1) and (HR: 0.86, 95%CI: 0.80-0.93 per 1L increase in FVC)]. Compared to normal lung function, restrictive disease was associated with elevated dementia risk [(HR: 1.19, 95%CI: 1.01-1.41), n=168 dementia cases]; HR for obstructive disease, though modestly elevated (1.09, 95%CI: 0.96-1.24, n=713 dementia cases), was not statistically significant. Our findings of decreased dementia risk with better lung function may have important implications in reducing burden of dementia that is attributable to environmental exposures and associated lung function impairment.

Introduction The aim was to examine associations between midlife cardiovascular health (CVH) and 20-year cognitive decline among blacks and whites. Methods Midlife CVH metrics (American Heart Association's Life's Simple 7) were calculated and examined in relation to midlife and 20-year change in cognitive function among 13,270 whites and blacks from the Atherosclerosis Risk in Communities Cohort Study. We used linear mixed models to estimate adjusted associations of midlife CVH with midlife cognitive status and change. Results Higher midlife (Life's Simple 7) scores and individual metrics, particularly blood pressure and glucose, were associated with better midlife cognition and reduced 20-year decline. Midlife CVH 20-year neuroprotection was more pronounced among whites than blacks. Discussion Better midlife CVH was associated with higher midlife and reduced decline in cognitive function 20 years later. However, the benefits of midlife CVH on cognition were stronger for whites than for blacks. Our findings suggest that improved midlife CVH may promote enduring cognitive health.

AIM Osteoprotegerin (OPG) is associated with a poor prognosis in patients with heart failure with preserved ejection fraction (HFpEF). OPG has also been associated with fibrosis and collagen cross-linking, which increase arterial and left ventricle (LV) myocardial stiffness. Little is known about the relation of OPG and LV structure and function in African-Americans who are disproportionately affected by HFpEF. METHODS AND RESULTS Our analysis included 1172 participants with preserved LV ejection fraction (>50%) from the African-American cohort in the Genetic Epidemiology Network of Arteriopathy Study (mean age 63 years, 72% female). We used diastolic wall strain indicator measured by echocardiography to assess LV myocardial stiffness. Diastolic wall strain was calculated as (LV posterior thickness at end-systole - LV posterior thickness at end-diastole)/LV posterior thickness at end-systole. Associations between OPG levels and indices of arterial and LV structure and function were evaluated by using generalized linear mixed models and adjusted for possible confounders. OPG levels were correlated with age, female sex, presence of hypertension and diabetes, and lower estimated glomerular filtration rate (P

Background and Purpose— Cerebral microbleed (CMB) location (deep versus strictly lobar) may elucidate underlying pathology with deep CMBs being more associated with hypertensive vascular disease and lobar CMBs being more associated with cerebral amyloid angiopathy. The objective of this study was to determine whether neuroimaging signs of vascular disease and Alzheimer pathology are associated with different types of CMBs. Methods— Among 1677 nondemented ARIC (Atherosclerosis Risk in Communities) participants (mean age=76±5 years; 40% men; 26% black) with 3-Tesla MRI scans at the fifth examination (2011–2013), we fit multinomial logistic regression models to quantify relationships of brain volumes (Alzheimer disease signature regions, total gray matter, frontal gray matter, and white matter hyperintensity volumes), infarct frequencies (lacunar, nonlacunar, and total), and apolipoprotein E (number of ε4 alleles) with CMB location (none, deep/mixed, or strictly lobar CMBs). Models were weighted for the sample selection scheme and adjusted for age, sex, education, hypertension, ever smoking status, diabetes mellitus, race site membership, and estimated intracranial volume (brain volume models only). Results— Deep/mixed and strictly lobar CMBs had prevalences of 8% and 16%, respectively. Larger white matter hyperintensity burden, greater total infarct frequency, smaller frontal volumes (in women only), and smaller total gray matter volume were associated with greater risk of both deep and lobar CMBs relative to no CMBs. Greater white matter hyperintensity volume was also associated with greater risk of deep relative to lobar CMBs. Higher lacunar and nonlacunar infarct frequencies were associated with higher risk of deep CMBs, whereas smaller Alzheimer disease signature region volume and apolipoprotein E ε4 homozygosity were associated with greater risk of lobar CMBs. Conclusions— CMBs are a common vascular pathology in the elderly. Markers of hypertensive small-vessel disease may contribute to deep CMBs while cerebral amyloid angiopathy may drive development of lobar CMBs.

Background and aims In European descent populations, shorter leukocyte telomere length (LTL) has been associated with subclinical atherosclerosis, cardiovascular disease (CVD), and mortality, while longer LTL has been associated with greater left ventricular hypertrophy. We evaluated the relationship of LTL with subclinical cardiovascular disease indices and incident clinical events and mortality in African Americans (AAs). Methods Analyses were restricted to 2518 participants of the Jackson Heart Study (JHS) with LTL measured by Southern blot in baseline blood samples. Results Adjusting for established CVD risk factors, longer LTL was significantly associated with lower prevalence of coronary artery calcification (CAC) (odds ratio (OR) = 0.810) per 1 kb increase in LTL; (95% confidence interval [CI] 0.656, 0.9998), p=0.0498). Longer LTL was also associated with higher ankle brachial index (ABI) (β = 0.023; (95% CI 0.004, 0.042), p=0.017) when comparing the highest to the lowest LTL quartile. There were no significant associations between LTL and abdominal aortic calcification, carotid intima-media thickness, or left ventricular mass. After a median follow-up of 9 years, longer LTL was associated with lower risk of incident ischemic stroke (hazard ratio (HR) 0.69 (95% CI 0.48, 0.99), p=0.044) and total mortality (HR 0.81 (95% CI 0.67, 0.97), p=0.026) in age and sex adjusted models, but these associations were no longer significant in fully adjusted models. Conclusions Among a community-based cohort of AAs, longer LTL was nominally associated with lower odds of CAC and increased ABI, indicative of decreased prevalence of subclinical atherosclerosis and peripheral arterial disease. These findings do not offer strong support for LTL as an independent biomarker of CVD risk in AAs.

OBJECTIVE To examine the associations of prediabetes, diabetes, and diabetes severity (as assessed by HbA1c and diabetes duration) with brain volumes and vascular pathology on brain MRI and to assess whether the associations of diabetes with brain volumes are mediated by brain vascular pathology. RESEARCH DESIGN AND METHODS Cross-sectional study of 1,713 participants in the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS) (mean age 75 years, 60% female, 27% black, 30% prediabetes, and 35% diabetes) who underwent 3T brain MRI scans in 2011–2013. Participants were categorized by diabetes-HbA1c status as without diabetes ( RESULTS In adjusted analyses, compared with participants without diabetes and HbA1c 0.05), but those with diabetes and HbA1c ≥7.0% had smaller total brain volume (β −0.20 SDs, 95% CI −0.31, −0.09), smaller regional brain volumes (including frontal, temporal, occipital, and parietal lobes; deep gray matter; Alzheimer disease signature region; and hippocampus [all P < 0.05]), and increased burden of white matter hyperintensities (WMH) (P = 0.016). Among participants with diabetes, those with HbA1c ≥7.0% had smaller total and regional brain volumes and an increased burden of WMH (all P < 0.05) compared with those with HbA1c 0.05). CONCLUSIONS More-severe diabetes (defined by higher HbA1c and longer disease duration) but not prediabetes or less-severe diabetes was associated with smaller brain volumes and an increased burden of brain vascular pathology. No evidence was found that associations of diabetes with smaller brain volumes are mediated by brain vascular pathology, suggesting that other mechanisms may be responsible for these associations.

Studies of major depressive disorder (MDD) in postmortem brain tissue report enhanced binding to inhibitory serotonin-1A autoreceptors in midbrain dorsal raphe and reductions in length of axons expressing the serotonin transporter (SERT) in dorsolateral prefrontal cortex. The length density of axons expressing SERT in the orbitofrontal cortex (OFC) was determined in 18 subjects with MDD and 17 age-matched control subjects. A monoclonal antibody was used to immunohistochemically label the SERT in fixed sections of OFC. The 3-dimensional length density of SERT-immunoreactive (ir) axons in layer VI of OFC was estimated. The age of subjects with MDD was negatively correlated with SERT axon length (r=−0.77, p

Background Adiposity depots may differentially affect cognition. African Americans (AA) have higher rates of obesity and dementia but lower visceral adipose tissue (VAT) than whites, yet are underrepresented in studies of adiposity and cognition. Our study compared relations of cognitive function to clinical adiposity measures and computed tomography (CT)-imaged abdominal adiposity in AA. Methods CT-imaged subcutaneous adipose tissue (SAT) and VAT measurements were obtained in the AA cohort of the Genetic Epidemiology Network of Arteriopathy Study (N = 652, mean age 68 ± 8.4 years, 74% females, 59% obese, 82% hypertensive). Clinical adiposity measures included waist circumference (WC) and body mass index (BMI). Global cognition was operationalized as a global cognitive z-score generated from the average of four cognitive domain z-scores. Generalized estimating equations were used to examine cross-sectional associations between individual standardized adiposity measures and cognition, accounting for age, sex, education, smoking status, and familial clustering. A collective model was constructed including multiple supported adiposity measures and age-by-adiposity interactions. Results In the collective model, higher WC was associated with worse global cognition, β = -0.12 (95%CI: -0.21, -0.03); higher SAT was associated with better cognition, β = 0.09 (0.01, 0.18); higher BMI was associated with worse cognition at younger ages with attenuation at older ages (BMI-by-age-interaction p = .004). VAT was not significantly associated with global cognition, β = -0.03 (-0.07, 0.02). Conclusions WC may be the simplest and most efficient measure of adiposity to assess with respect to cognition in clinical settings, although studies to determine mechanistic effects of subcutaneous and other adiposity depots on cognition are warranted.

Purpose To determine whether use of the liver surface nodularity (LSN) score, a quantitative biomarker derived from routine computed tomographic (CT) images, allows prediction of cirrhosis decompensation and death. Materials and Methods For this institutional review board-approved HIPAA-compliant retrospective study, adult patients with cirrhosis and Model for End-Stage Liver Disease (MELD) score within 3 months of initial liver CT imaging between January 3, 2006, and May 30, 2012, were identified from electronic medical records (n = 830). The LSN score was measured by using CT images and quantitative software. Competing risk regression was used to determine the association of the LSN score with hepatic decompensation and overall survival. A risk model combining LSN scores (

This report resulted from a working group assembled by the JHS (Jackson Heart Study) coordinating center as part of a symposium to identify, discuss, and refine key questions, related to hypertension in blacks, that can be addressed in the National Heart, Lung and Blood Institute (NHLBI)–sponsored study. The symposium and working group were assembled to assist in the preparation for the next phase of the JHS. The JHS is a longitudinal observational study designed to identify cardiovascular disease (CVD) risk factors among blacks and to develop the infrastructure for training the next generation of health disparities researchers.1 Between 2000 and 2004, 5306 community-dwelling blacks, aged ≥21 years, were enrolled from the tricounty area of Jackson, MS. In addition to a baseline study visit, follow-up visits were conducted in 2005 to 2008 and 2009 to 2013. JHS participants are contacted annually by telephone to identify potential CVD events that are adjudicated by trained clinicians.2 Hypertension is more common in blacks than any other race/ethnic group in the United States.3 In addition, blacks have a higher incidence of hypertension-related CVD and end-stage renal disease than other race/ethnic groups in the United States.4,5 The hypertension working group thought broadly about essential research questions related to hypertension in blacks. We considered research questions that could be addressed through continued observational follow-up of the JHS cohort or by conducting interventions among JHS participants. The working group benefited from reviewing the NHLBI Strategic Vision and a recently published report from an NHLBI working group addressing research needs to improve hypertension treatment and control in blacks.6,7 Also, this report builds on the published work in the area of hypertension from the JHS (Table 1). Some of the suggestions from the working group require new study visits and are …

Depression affects up to 30% of human immunodeficiency virus (HIV)-infected individuals. We estimated joint effects of antiretroviral therapy (ART) initiation and depressive symptoms on time to death using a joint marginal structural model and data from a cohort of HIV-infected women from the Women's Interagency HIV Study (conducted in the United States) from 1998–2011. Among 848 women contributing 6,721 years of follow-up, 194 participants died during follow-up, resulting in a crude mortality rate of 2.9 per 100 women-years. Cumulative mortality curves indicated greatest mortality for women who reported depressive symptoms and had not initiated ART. The hazard ratio for depressive symptoms was 3.38 (95% confidence interval (CI): 2.15, 5.33) and for ART was 0.47 (95% CI: 0.31, 0.70). Using a reference category of women without depressive symptoms who had initiated ART, the hazard ratio for women with depressive symptoms who had initiated ART was 3.60 (95% CI: 2.02, 6.43). For women without depressive symptoms who had not started ART, the hazard ratio was 2.36 (95% CI: 1.16, 4.81). Among women reporting depressive symptoms who had not started ART, the hazard ratio was 7.47 (95% CI: 3.91, 14.3). We found a protective effect of ART initiation on mortality, as well as a harmful effect of depressive symptoms, in a cohort of HIV-infected women.

Introduction: The prognosis of glioblastoma (GBM) treated with standard-of-care maximal surgical resection and concurrent adjuvant temozolomide (TMZ)/radiotherapy remains very poor (less than 15 months). GBMs have been found to contain a small population of cancer stem cells (CSCs) that contribute to tumor propagation, maintenance, and treatment resistance. The highly invasive nature of high-grade gliomas and their inherent resistance to therapy lead to very high rates of recurrence. For these reasons, not all patients with similar diagnoses respond to the same chemotherapy, schedule, or dose. Administration of ineffective anticancer therapy is not only costly but more importantly burdens the patient with unnecessary toxicity and selects for the development of resistant cancer cell clones. We have developed a drug response assay (ChemoID) that identifies the most effective chemotherapy against CSCs and bulk of tumor cells from of a panel of potential treatments, offering great promise for individualized cancer management. Providing the treating physician with drug response information on a panel of approved drugs will aid in personalized therapy selections of the most effective chemotherapy for individual patients, thereby improving outcomes. A prospective study was conducted evaluating the use of the ChemoID drug response assay in GBM patients treated with standard of care. Methods: Forty-one GBM patients (mean age 54 years, 59% male), all eligible for a surgical biopsy, were enrolled in an Institutional Review Board–approved protocol, and fresh tissue samples were collected for drug sensitivity testing. Patients were all treated with standard-of-care TMZ plus radiation with or without maximal surgery, depending on the status of the disease. Patients were prospectively monitored for tumor response, time to recurrence, progression-free survival (PFS), and overall survival (OS). Odds ratio (OR) associations of 12-month recurrence, PFS, and OS outcomes were estimated for CSC, bulk tumor, and combined assay responses for the standard-of-care TMZ treatment; sensitivities/specificities, areas under the curve (AUCs), and risk reclassification components were examined. Results: Median follow-up was 8 months (range 3-49 months). For every 5% increase in in vitro CSC cell kill by TMZ, 12-month patient response (nonrecurrence of cancer) increased two-fold, OR=2.2 ( P =.016). Similar but somewhat less supported associations with the bulk tumor test were seen, OR=2.75 ( P =.07) for each 5% bulk tumor cell kill by TMZ. Combining CSC and bulk tumor assay results in a single model yielded a statistically supported CSC association, OR=2.36 ( P =.036), but a much attenuated remaining bulk tumor association, OR=1.46 ( P =.472). AUCs and [sensitivity/specificity] at optimal outpoints (>40% CSC cell kill and >55% bulk tumor cell kill) were AUC=0.989 [sensitivity=100/specificity=97], 0.972 [100/89], and 0.989 [100/97] for the CSC only, bulk tumor only, and combined models, respectively. Risk categorization of patients was improved by 11% when using the CSC test in conjunction with the bulk test (risk reclassification nonevent net reclassification improvement [NRI] and overall NRI=0.111, P =.030). Median recurrence time was 20 months for patients with a positive (>40% cell kill) CSC test versus only 3 months for those with a negative CSC test, whereas median recurrence time was 13 months versus 4 months for patients with a positive (>55% cell kill) bulk test versus negative. Similar favorable results for the CSC test were observed for PFS and OS outcomes. Panel results across 14 potential other treatments indicated that 34/41 (83%) potentially more optimal alternative therapies may have been chosen using CSC results, whereas 27/41 (66%) alternative therapies may have been chosen using bulk tumor results. Conclusions: The ChemoID CSC drug response assay has the potential to increase the accuracy of bulk tumor assays to help guide individualized chemotherapy choices. GBM cancer recurrence may occur quickly if the CSC test has a low in vitro cell kill rate even if the bulk tumor test cell kill rate is high.

Objectives This study sought to assess whether body mass index (BMI) was associated with subclinical left ventricular (LV) systolic dysfunction in African-American individuals. Background Higher BMI is a risk factor for cardiovascular disease, including heart failure. Obesity disproportionately affects African Americans; however, the association between higher BMI and LV function in African Americans is not well understood. Methods Peak systolic circumferential strain (ECC) was measured by tagged cardiac magnetic resonance in 1,652 adult African-American participants of the Jackson Heart Study between 2008 and 2012. We evaluated the association between BMI and ECC in multivariate linear regression and restricted cubic spline analyses adjusted for prevalent cardiovascular disease, conventional cardiovascular risk factors, LV mass, and ejection fraction. In exploratory analyses, we also examined whether inflammation, insulin resistance, or volume of visceral adipose tissue altered the association between BMI and ECC. Results The proportions of female, nonsmokers, diabetic, and hypertensive participants rose with increase in BMI. In multivariate-adjusted models, higher BMI was associated with worse ECC (β = 0.052; 95% confidence interval: 0.028 to 0.075), even in the setting of preserved LV ejection fraction. Higher BMI was also associated with worse ECC when accounting for markers of inflammation (C-reactive protein, E-selection, and P-selectin), insulin resistance, and volume of visceral adipose tissue. Conclusions Higher BMI is significantly associated with subclinical LV dysfunction in African Americans, even in the setting of preserved LV ejection fraction.

Plasma-based biomarkers of amyloid beta (Aβ), a neuropathological hallmark of Alzheimer’s disease, show promise in predicting cognitive impairment and mapping onto cerebral amyloidosis, but little is known about how midlife plasma Aβ associates with late-life cognitive outcomes. Midlife plasma variants Aβ42 and Aβ40 were measured using a fluorimetric bead-based immunoassay in a subsample of visit 3 ARIC participants (1993-95; n=2585, mean age=59.4±5.2, 57% female, 23% African American). We investigated the relationship between midlife plasma Aβ and late-life mild cognitive impairment (MCI; n=923) and dementia (n=628) diagnosed from 2011-19. Multinomial logistic regressions estimated relative risk ratios (RRR) of MCI, dementia, and death vs normal cognitive status as a function of:(1) Aβ42:Aβ40 ratio, (2) Aβ42 and Aβ40 included as separate terms, and (3) Protected Aβ group (participants with Aβ42≥46 pg/ml and Aβ40

Few studies examined race-regional influences on mild cognitive impairment (MCI) and dementia risk factors. We examined 14 risk factors in 5 race-regions, e.g. cross-sectional age- and sex-adjusted relative prevalence ratios (RPR) from multinomial regression comparing associations of low education (

Background There is growing evidence that Alzheimer disease (AD) is a pervasive metabolic disorder with dysregulation in multiple biochemical pathways underlying its pathogenesis. Understanding how perturbations in metabolism are related to AD is critical to identifying novel targets for disease-modifying therapies. In this study, we test whether AD pathogenesis is associated with dysregulation in brain transmethylation and polyamine pathways. Methods and findings We first performed targeted and quantitative metabolomics assays using capillary electrophoresis-mass spectrometry (CE-MS) on brain samples from three groups in the Baltimore Longitudinal Study of Aging (BLSA) (AD: n = 17; Asymptomatic AD [ASY]: n = 13; Control [CN]: n = 13) (overall 37.2% female; mean age at death 86.118 ± 9.842 years) in regions both vulnerable and resistant to AD pathology. Using linear mixed-effects models within two primary brain regions (inferior temporal gyrus [ITG] and middle frontal gyrus [MFG]), we tested associations between brain tissue concentrations of 26 metabolites and the following primary outcomes: group differences, Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) (neuritic plaque burden), and Braak (neurofibrillary pathology) scores. We found significant alterations in concentrations of metabolites in AD relative to CN samples, as well as associations with severity of both CERAD and Braak, mainly in the ITG. These metabolites represented biochemical reactions in the (1) methionine cycle (choline: lower in AD, p = 0.003; S-adenosyl methionine: higher in AD, p = 0.005); (2) transsulfuration and glutathione synthesis (cysteine: higher in AD, p < 0.001; reduced glutathione [GSH]: higher in AD, p < 0.001); (3) polyamine synthesis/catabolism (spermidine: higher in AD, p = 0.004); (4) urea cycle (N-acetyl glutamate: lower in AD, p < 0.001); (5) glutamate-aspartate metabolism (N-acetyl aspartate: lower in AD, p = 0.002); and (6) neurotransmitter metabolism (gamma-amino-butyric acid: lower in AD, p < 0.001). Utilizing three Gene Expression Omnibus (GEO) datasets, we then examined mRNA expression levels of 71 genes encoding enzymes regulating key reactions within these pathways in the entorhinal cortex (ERC; AD: n = 25; CN: n = 52) and hippocampus (AD: n = 29; CN: n = 56). Complementing our metabolomics results, our transcriptomics analyses also revealed significant alterations in gene expression levels of key enzymatic regulators of biochemical reactions linked to transmethylation and polyamine metabolism. Our study has limitations: our metabolomics assays measured only a small proportion of all metabolites participating in the pathways we examined. Our study is also cross-sectional, limiting our ability to directly test how AD progression may impact changes in metabolite concentrations or differential-gene expression. Additionally, the relatively small number of brain tissue samples may have limited our power to detect alterations in all pathway-specific metabolites and their genetic regulators. Conclusions In this study, we observed broad dysregulation of transmethylation and polyamine synthesis/catabolism, including abnormalities in neurotransmitter signaling, urea cycle, aspartate-glutamate metabolism, and glutathione synthesis. Our results implicate alterations in cellular methylation potential and increased flux in the transmethylation pathways, increased demand on antioxidant defense mechanisms, perturbations in intermediate metabolism in the urea cycle and aspartate-glutamate pathways disrupting mitochondrial bioenergetics, increased polyamine biosynthesis and breakdown, as well as abnormalities in neurotransmitter metabolism that are related to AD., Uma Mahajan and coworkers study metabolic perturbations in specific brain regions in Alzheimer disease., Author summary Why was this study done? A growing body of evidence suggests that Alzheimer disease (AD) may be associated with dysregulation of multiple metabolic pathways, and identifying novel molecular targets underlying AD pathogenesis is essential for developing effective AD treatments. Past studies have shown that abnormalities in choline-related biochemical pathways may be associated with AD pathogenesis, specifically the transmethylation, polyamine synthesis/catabolism and related pathways. Our study tested the hypothesis that dysregulation of choline-related biochemical pathways in the brain is associated with AD pathogenesis; we examined metabolites within biochemical reactions linked to transmethylation and polyamine synthesis/catabolism. What did the researchers do and find? We performed quantitative and targeted metabolomics on brain tissue samples (AD: n = 17; Asymptomatic AD [ASY]: n = 13; Control [CN]: n = 13) and transcriptomics from Gene Expression Omnibus data (entorhinal cortex [AD: n = 25; CN: n = 52] and hippocampus [AD: n = 29; CN: n = 56]) to identify aberrations across 6 biochemical reactions linked to the transmethylation and polyamine pathways: methionine cycle, transsulfuration and glutathione synthesis, polyamine synthesis and catabolism, urea cycle, glutamate-aspartate metabolism, and neurotransmitter metabolism. We found significant metabolite alterations associated with AD mainly in the inferior temporal gyrus (ITG) across all pathways tested, as well as associations between metabolite concentrations and severity of AD pathology. Complementing our metabolomics results, our transcriptomics analyses also revealed significant alterations in gene expression of key enzymatic regulators of biochemical reactions linked to transmethylation and polyamine metabolism. What do these findings mean? Our results implicate alterations in cellular methylation potential and increased flux in the transmethylation pathways, increased demand on antioxidant defense mechanisms, perturbations in intermediate metabolism in the urea cycle and aspartate-glutamate pathways disrupting mitochondrial bioenergetics, increased polyamine biosynthesis and breakdown, as well as abnormalities in neurotransmitter metabolism that are related to severity of AD pathology and the expression of clinical symptoms. This study adds to a comprehensive understanding of the metabolic basis of AD pathogenesis and provides insights into novel targets for disease-modifying therapies. The cross-sectional nature of the study limits our ability to directly test how AD progression may impact changes in metabolite concentrations or differential-gene expression.

Background Smaller (

BACKGROUND: In longitudinal research studies with follow-up examinations, the devices used to measure phenotypes may change over time. When a device change occurs, the two devices should be calibrated to each other to ensure that measurements are comparable. This paper details the Jackson Heart Study (JHS) blood pressure (BP) comparability study. METHODS: During its second clinic exam (2005–2008), the JHS switched from a random-zero sphygmomanometer (RZS) BP measurement device to an oscillometric device (OD). During this exam, BP measurements from both a RZS and an OD were taken simultaneously in 2,117 participants for the purpose of calibration. Five methods for calibrating systolic BP (SBP) and diastolic BP (DBP) were considered: ignoring the change, ordinary least squares regression, adding the average difference, Deming regression, and robust regression. RESULTS: Using the RZS and OD, the mean (standard deviation) SBP was 125.5 (19.2) and 126.5 (19.9), respectively, and the mean (standard deviation) DBP was 76.4 (10.6) and 74.0 (11.0), respectively. The correlation between RZS and the OD was 0.90 for SBP and 0.80 for DBP. The prevalence of high BP and hypertension and associations with albuminuria were similar when applying each of the five calibration methods. Robust regression was chosen for calibration, giving the following equations: [Formula: see text] [Formula: see text] These equations had a higher R(2) statistic than using calibration equations from the Coronary Artery Risk Development in Young Adults Study and the Heinz Nixdorf Recall Study. CONCLUSIONS: The JHS BP data has been calibrated using the above equations for use in future analyses.

ObjectiveAfrican Americans, especially those in the Southeastern USA, have different dietary behaviours from the general US population, and have the highest prevalence, incidence and mortality of diet-related disease outcomes, such as cardiovascular disease. However, there are scant data regarding factors such as socioeconomic position (SEP) across the life course that influence dietary behaviours in this high-risk population. Our aim was to examine the impact of life course and neighbourhood SEPs on dietary intake among African Americans.Participants and settingData for this cross-sectional analysis came from the community-based Jackson Heart Study (JHS). We analysed a total of 3948 JHS participants (mean age: 55.4±12.5; 63.9% women), who had complete dietary intake and covariate information.MethodsWe examined the associations of childhood SEP (CSEP), adulthood SEP (ASEP) and neighbourhood SEP (NSEP) with 10 selected dietary intake measures, using multilevel log-gamma generalised linear regression models.Outcome measuresDietary intake measures include daily saturated fat, sodium, protein, fibre, fruits and vegetables, whole grains, sugar-sweetened beverage, nuts, fish and processed meat.ResultsIn age, sex and total energy intake adjusted models, most dietary intakes were associated with these three SEP measures. After additional adjustment for other SEP measures, most of the significant associations with CSEP and NSEP were attenuated, except for the associations of fibre with CSEP (relative rate [RR] [95% CI] 1.05 [1.00–1.10]) and whole grains with NSEP (RR [95% CI] 1.28 [1.02–1.61]). The associations (shown as RR [95% CI]) between ASEP and sugar-sweetened beverage: 0.70 (0.59–0.83), processed meat: 0.75 (0.63–0.90), sodium: 0.99 (0.94–1.00), fibre: 1.10 (1.03–1.16), protein: 1.05 (1.01–1.09), fruits and vegetables: 1.21 (1.11–1.32), nuts: 2.13 (1.59–2.87), and fish: 1.57 (1.27–1.95) generally persisted after additional adjustment for both CSEP and NSEP. However, the association between ASEP and whole grains was attenuated.ConclusionsHigh ASEP may have a more beneficial influence on dietary practices in African Americans than CSEP or NSEP.

Background: Smoking is a risk factor for vascular diseases and likely associated with cognitive decline. However, observed associations may be impacted by higher cohort attrition, particularly mortality, among smokers. We incorporated surveillance data between visits using multiple imputation by chained equations (MICE) and assumed the Missing At Random mechanism in missing cognitive function. We assessed the impact of addressing the influence of differential visit attendance driven by mortality on the association of smoking with cognitive decline. Methods: We studied 4,960 participants in Atherosclerosis Risk in Communities (ARIC) Neurocognitive Study, who were free from dementia at baseline (2011-2013) with cognitive batteries at baseline and follow-up (2016-2017, N = 3,078). Cognitive decline was measured as change in standardized global cognitive factor scores. Self-reported smoking was collected at previous visits (1987-1998) and annual follow-up interviews (1998 to 2011) of the ARIC study, and pack years were estimated. We used baseline factor scores, dementia risk factors, and cognitive function screening at annual follow-ups and dementia surveillance information after baseline to impute missing factor scores. Cognitive decline was analyzed using linear regression on both complete data and using MICE. Results: Participants had a mean age of 75.7 (SD: 5.1) at the index visit. 59.6% (2956 of 4960) were female and 18.6% (921 of 4960) were African American. Smoking ≥25 pack-years prior to baseline was associated with moderately lower visit attendance and higher mortality at older age. The association of smoking with cognitive decline was stronger after addressing differential attrition driven by mortality using MICE for smoking ≥25 pack-years, with two-fold increase in the effect size (Table 1). Conclusions: Smoking, particularly of longer duration and intensity, is a risk factor for cognitive decline, with larger effect size when dealing with the differentially higher mortality among heavier smokers.

Background and objectives The joint modeling of longitudinal and survival data to assess effects of multiple informative dropout mechanisms on longitudinal outcomes inference has received considerable attention during recent years; related statistical programs to apply these methods have been lacking. This paper provides a SAS macro implementation of a shared parameter model to accommodate the analysis of longitudinal outcomes in the presence of multiple competing survival/dropout events. Methods In this macro, we assumed that the associations between the survival and the longitudinal submodels are linked through a set of shared random effects. The submodel for the longitudinal outcome takes the form of a linear mixed effects model, with specifications for the random intercept and/or random slope. The survival submodel allows up to three different competing causes for dropout, each allowing either an exponential or Weibull parametric baseline hazard function. In addition, information criterion fit statistics AIC and BIC are provided to assist with parametric baseline hazard function selection. Results We illustrate the SAS Macro in a cognitive decline study sensitivity analysis using data from the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS). In addition, we also conduct a simulation study to show that the joint model provides unbiased parameter estimates when informative dropout exists compared against separate model approach which assumes missing at random dropout mechanisms. Conclusions We have presented a SAS macro to implement a shared parameter model for a longitudinal outcome and multiple cause-specific dropouts and made the macro code freely available for download.

Genome-wide studies (GWS) of SNP associations and differential gene expressions have generated abundant results; next-generation sequencing technology has further boosted the number of variants and genes identified. Effective interpretation requires massive annotation and downstream analysis of these genome-wide results, a computationally challenging task. We developed the snpGeneSets package to simplify annotation and analysis of GWS results. Our package integrates local copies of knowledge bases for SNPs, genes, and gene sets, and implements wrapper functions in the R language to enable transparent access to low-level databases for efficient annotation of large genomic data. The package contains functions that execute three types of annotations: (1) genomic mapping annotation for SNPs and genes and functional annotation for gene sets; (2) bidirectional mapping between SNPs and genes, and genes and gene sets; and (3) calculation of gene effect measures from SNP associations and performance of gene set enrichment analyses to identify functional pathways. We applied snpGeneSets to type 2 diabetes (T2D) results from the NHGRI genome-wide association study (GWAS) catalog, a Finnish GWAS, and a genome-wide expression study (GWES). These studies demonstrate the usefulness of snpGeneSets for annotating and performing enrichment analysis of GWS results. The package is open-source, free, and can be downloaded at: https://www.umc.edu/biostats_software/.

Genome-wide association study (GWAS) has been successful in identifying obesity risk genes by single-variant association analysis. For this study, we designed steps of analysis strategy and aimed to identify multi-variant effects on obesity risk among candidate genes.Our analyses were focused on 2137 African American participants with body mass index measured in the Jackson Heart Study and 657 common single nucleotide polymorphisms (SNPs) genotyped at 8 GWAS-identified obesity risk genes.Single-variant association test showed that no SNPs reached significance after multiple testing adjustment. The following gene-gene interaction analysis, which was focused on SNPs with unadjusted p-value0.10, identified 6 significant multi-variant associations. Logistic regression showed that SNPs in these associations did not have significant linear interactions; examination of genetic risk score evidenced that 4 multi-variant associations had significant additive effects of risk SNPs; and haplotype association test presented that all multi-variant associations contained one or several combinations of particular alleles or haplotypes, associated with increased obesity risk.Our study evidenced that obesity risk genes generated multi-variant effects, which can be additive or non-linear interactions, and multi-variant study is an important supplement to existing GWAS for understanding genetic effects of obesity risk genes.

Purpose To quantify initial changes in the vascular tumor burden (VTB), a measure of the area of vascularized tumor on computed tomographic (CT) images, and predict tumor response to antiangiogenic therapy in patients with metastatic renal cell carcinoma (RCC). Materials and Methods For this institutional review board-approved HIPAA-compliant secondary analysis of a prospective phase III trial, adult patients with digital CT images and metastatic clear-cell RCC treated with sunitinib were included (n = 275). Target lesions were selected by using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 guidelines, and the CT images obtained after one cycle of sunitinib therapy were evaluated in comparison with baseline images. Tumor-response software was created to quantify tumor metrics (length, area, VTB, and mean attenuation) and automate response assessment. Progression-free survival (PFS) in responders and nonresponders according to VTB criteria was compared by using the Cox proportional hazard ratio (HR). The intraclass correlation coefficient (ICC) was used to assess interobserver agreement among three readers evaluating 28 randomly selected patients. Results VTB criteria nonresponders (n = 120) according to the initial posttherapy CT study were 5.7 times more likely to experience progression of disease (HR = 5.70; 95% confidence interval [CI]: 4.07, 7.97; P < .001) than responders (n = 155). There was not a statistically significant difference in PFS between RECIST nonresponders (n = 255) and responders (n = 20; HR = 1.54; 95% CI: 0.85, 2.77; P = .148). In a patient-level analysis, interobserver agreement was very good for assessing percentage change in length, area, and VTB (ICC = 0.82 [95% CI: 0.67, 0.91], 0.89 [95% CI: 0.79, 0.94], and 0.88 [95% CI: 0.79, 0.94], respectively) but was very poor for assessing percentage change in mean attenuation (ICC = 0.17 [95% CI: -0.05, 0.45]). Conclusion A quantitative CT imaging biomarker designed to measure initial changes in the VTB separated patients into responders and nonresponders, each with significantly different PFS, and showed very good interobserver agreement in patients with metastatic RCC treated with sunitinib. © RSNA, 2016 Online supplemental material is available for this article.

Introduction The epidemiology of American Heart Association ideal cardiovascular health (CVH) metrics has not been fully examined in African Americans. This study examines the associations of CVH metrics with incident cardiovascular disease (CVD) in the Jackson Heart Study, a longitudinal cohort study of CVD in African Americans. Methods Jackson Heart Study participants without CVD ( n =4,702) were followed prospectively between 2000 and 2011. Incidence rates and Cox proportional hazard ratios estimated risks for incident CVD (myocardial infarction, stroke, cardiac procedures, and CVD mortality) associated with seven CVH metrics by sex. Analyses were performed in 2015. Results Participants were followed for a median of 8.3 years; none had ideal health on all seven CVH metrics. The prevalence of ideal health was low for nutrition, physical activity, BMI, and blood pressure metrics. The age-adjusted CVD incidence rate (IR) per 1,000 person years was highest for individuals with the least ideal health metrics: zero to one (IR=12.5, 95% CI=9.7, 16.1), two (IR=8.2, 95% CI=6.5, 10.4), three (IR=5.7, 95% CI=4.2, 7.6), and four or more (IR=3.4, 95% CI=2.0, 5.9). Adjusting for covariates, individuals with four or more ideal CVH metrics had lower risks of incident CVD compared with those with zero or one ideal CVH metric (hazard ratio, 0.29; 95% CI=0.17, 0.52; p Conclusions African Americans with more ideal CVH metrics have lower risks of incident CVD. Comprehensive preventive behavioral and clinical supports should be intensified to improve CVD risk for African Americans with few ideal CVH metrics.

Objectives To quantify associations between inflammatory biomarkers and hippocampal volume (HV) and to examine effect modification according to sex, race, and age. Design Cross-sectional analyses using generalized estimating equations to account for familial clustering; standardized β-coefficients adjusted for age, sex, race, and education. Setting Community cohorts in Jackson, Mississippi and Rochester, Minnesota. Participants The Genetic Epidemiology Network of Arteriopathy study. Measurements C-reactive protein (CRP), interleukin-6 (IL-6), and soluble tumor necrosis factor receptors 1 (sTNFR-1) and 2 (sTNFR-2) from peripheral blood were measured in a sample of 773 non-Hispanic whites (61% women, aged 60.2 ± 9.8) and 514 African Americans (70% women, aged 63.9 ± 8.1) who also underwent brain magnetic resonance imaging. Biomarkers were standardized and compared according to sex, race and age with HV. Results In the full sample, higher sTNFR-1 and sTNFR-2 were associated with smaller HV. Each standard deviation (SD) increase in sTNFR-1 was associated with 59.1 mm3 (95% confidence interval (CI) = −101.4 to −16.7 mm3) smaller HV and each SD increase in sTNFR-2 associated with 48.8 mm3 (95% CI = −92.2 to −5.3 mm3) smaller HV. Relationships were stronger for sTNFR-2 in men (HV = −116.6 mm3 for each SD increase, 95% CI = −201.0 to −32.1) than women (HV = −26.0 per SD increase, 95% CI = −72.4–20.5) and sTNFR-1 in non-Hispanic whites (HV = −84.7 mm3 per SD increase, 95% CI = −142.2 to −27.1) than African Americans (HV = −14.1 mm3 per SD increase, 95% CI = −78.3–50.1). Associations between IL-6 or CRP and HV were not supported. Conclusion Higher levels of sTNFRs were associated cross-sectionally with smaller hippocampi. Longitudinal data are needed to determine whether these biomarkers may help to identify risk of late-life cognitive impairment.

The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.

Background— The correlation of null alleles with human phenotypes can provide insight into gene function in humans. In individuals of African ancestry, we set out to identify null and damaging missense variants, and test these variants for association with a range of cardiovascular phenotypes. Methods and Results— We performed whole-exome sequencing in 3223 black individuals from the Jackson Heart Study and found a total of 729 666 variant sites with minor allele frequency −7 ). Null and damaging missense variants in PCSK9 were associated with 36 mg/dL lower low-density lipoprotein cholesterol ( P =3×10 −21 ). Three individuals in their 50s with complete PCSK9 deficiency (each compound heterozygote for PCSK9 p.Y142X and p.C679X) were identified, with one having a coronary artery calcification score in the 83rd percentile despite a low-density lipoprotein cholesterol of 32 mg/dL. A damaging missense variant in HBQ1 (p.G52A) was associated with a 2 pg/cell lower mean corpuscular hemoglobin ( P =9×10 −13 ) and rare damaging missense variants in VPS13A with higher red blood cell distribution width ( P =9.9×10 –8 ). Conclusions— A limited number of null/damaging alleles with a large effect on cardiovascular traits were detectable in ≈3000 black individuals.

The random effect Tobit model is a regression model that accommodates both left- and/or right-censoring and within-cluster dependence of the outcome variable. Regression coefficients of random effect Tobit models have conditional interpretations on a constructed latent dependent variable and do not provide inference of overall exposure effects on the original outcome scale. Marginalized random effects model (MREM) permits likelihood-based estimation of marginal mean parameters for the clustered data. For random effect Tobit models, we extend the MREM to marginalize over both the random effects and the normal space and boundary components of the censored response to estimate overall exposure effects at population level. We also extend the 'Average Predicted Value' method to estimate the model-predicted marginal means for each person under different exposure status in a designated reference group by integrating over the random effects and then use the calculated difference to assess the overall exposure effect. The maximum likelihood estimation is proposed utilizing a quasi-Newton optimization algorithm with Gauss-Hermite quadrature to approximate the integration of the random effects. We use these methods to carefully analyze two real datasets. Copyright © 2016 John Wiley & Sons, Ltd.

Objectives To examine associations between inflammation and physical function and potential mediation by white matter hyperintensities (WMHs) in African Americans (AAs) and European Americans (EAs). Design Cross-sectional analysis using linear and logistic models with generalized estimating equations to account for family clustering, reporting results as regression coefficients (β) and odds ratios (ORs) adjusted for education, alcohol, exercise, body mass index, hypertension, diabetes mellitus, heart disease, cognition, ankle–brachial index, race (site), and supported interactions. Setting Genetic Epidemiology Network of Arteriopathy-Genetics of Microangiopathic Brain Injury Study cohort. Participants AA and EA sibships with two or more siblings with hypertension before age 60 (N = 1,960; 65% female, 51% AA, aged 26–91, 50% obese, 72% hypertensive). Measurements Inflammation (C-reactive protein (CRP), interleukin-6 (IL6), soluble tumor necrosis factor receptors (sTNFRs) 1 and 2, WMH volume (cm3) according to magnetic resonance imaging), walking speed (cm/s) over 25 feet, and mobility difficulty (any self-reported difficulty walking half a mile). Results In separate models, inflammatory markers were associated with walking speed (sTNFR1: β = −2.74, P < .001; sTNFR2: β = −1.23, P = .03; CRP: β = −1.95, P = .001; IL6: β = −1.24, P = .03) and mobility difficulty (sTNFR1: OR = 1.36, P = .001; sTNFR2: OR = 1.25, P = .005; CRP: OR = 1.22, P = .005; IL6: OR = 1.18, P = .02); the association between WMH volume and sTNFR1 in AA (β = 0.07, P = .06) did not reach typical statistical thresholds. WMH volume was associated with walking speed in AA (β = −3.17, P = .02) but not with mobility difficulty (OR = 1.10, P = .54). Adjusting for WMH did not change associations. Conclusion In young, middle-aged, and older adults with prevalent cardiovascular risk factors, multiple inflammatory biomarkers were associated with slower walking speed independent of microvascular disease in the brain. There was little evidence of mediation by brain WMH volume. Inflammation may contribute to physical function impairments through pathways other than brain microvascular disease, particularly in AAs.

Background Genetic determinants of stroke, the leading neurological cause of death and disability, are poorly understood and have seldom been explored in the general population. Our aim was to identify additional loci for stroke by doing a meta-analysis of genome-wide association studies. Methods For the discovery sample, we did a genome-wide analysis of common genetic variants associated with incident stroke risk in 18 population-based cohorts comprising 84 961 participants, of whom 4348 had stroke. Stroke diagnosis was ascertained and validated by the study investigators. Mean age at stroke ranged from 45·8 years to 76·4 years, and data collection in the studies took place between 1948 and 2013. We did validation analyses for variants yielding a significant association (at p−6) with all-stroke, ischaemic stroke, cardioembolic ischaemic stroke, or non-cardioembolic ischaemic stroke in the largest available cross-sectional studies (70 804 participants, of whom 19 816 had stroke). Summary-level results of discovery and follow-up stages were combined using inverse-variance weighted fixed-effects meta-analysis, and in-silico lookups were done in stroke subtypes. For genome-wide significant findings (at p−8), we explored associations with additional cerebrovascular phenotypes and did functional experiments using conditional (inducible) deletion of the probable causal gene in mice. We also studied the expression of orthologs of this probable causal gene and its effects on cerebral vasculature in zebrafish mutants. Findings We replicated seven of eight known loci associated with risk for ischaemic stroke, and identified a novel locus at chromosome 6p25 (rs12204590, near FOXF2) associated with risk of all-stroke (odds ratio [OR] 1·08, 95% CI 1·05–1·12, p=1·48 × 10−8; minor allele frequency 21%). The rs12204590 stroke risk allele was also associated with increased MRI-defined burden of white matter hyperintensity—a marker of cerebral small vessel disease—in stroke-free adults (n=21 079; p=0·0025). Consistently, young patients (aged 2–32 years) with segmental deletions of FOXF2 showed an extensive burden of white matter hyperintensity. Deletion of Foxf2 in adult mice resulted in cerebral infarction, reactive gliosis, and microhaemorrhage. The orthologs of FOXF2 in zebrafish (foxf2b and foxf2a) are expressed in brain pericytes and mutant foxf2b−/− cerebral vessels show decreased smooth muscle cell and pericyte coverage. Interpretation We identified common variants near FOXF2 that are associated with increased stroke susceptibility. Epidemiological and experimental data suggest that FOXF2 mediates this association, potentially via differentiation defects of cerebral vascular mural cells. Further expression studies in appropriate human tissues, and further functional experiments with long follow-up periods are needed to fully understand the underlying mechanisms. Funding NIH, NINDS, NHMRC, CIHR, European national research institutions, Fondation Leducq.

Objectives/Hypothesis To evaluate the relationships among measures of physical activity and hearing in the Jackson Heart Study. Study Design Prospective cohort study. Methods We assessed hearing on 1,221 Jackson Heart Study participants who also had validated physical activity questionnaire data on file. Hearing thresholds were measured across frequency octaves from 250 to 8,000 Hz, and various frequency pure-tone averages (PTAs) were constructed, including PTA4 (average of 500, 1,000, 2,000, and 4,000 Hz), PTA-high (average of 4,000 and 8,000 Hz), PTA-mid (average of 1,000 and 2,000 Hz), and PTA-low (average of 250 and 500 Hz). Hearing loss was defined for pure tones and pure-tone averages as >25 dB HL in either ear and averaged between the ears. Associations between physical activity and hearing were estimated using linear regression, reporting changes in decibel hearing level, and logistic regression, reporting odds ratios (OR) of hearing loss. Results Physical activity exhibited a statistically significant but small inverse relationship with PTA4, −0.20 dB HL per doubling of activity (95% confidence interval [CI]: −0.35, −0.04; P = .016), as well as with PTA-low and pure tones at 250, 2,000, and 4,000 Hz in adjusted models. Multivariable logistic regression modeling supported a decrease in the odds of high-frequency hearing loss among participants who reported at least some moderate weekly physical activity (PTA-high, OR: 0.69 [95% CI: 0.52, 0.92]; P = .011 and 4000 Hz, OR: 0.75 [95% CI: 0.57, 0.99]; P = .044). Conclusions Our study provides further evidence that physical activity is related to better hearing; however, the clinical significance of this relationship cannot be estimated given the nature of the cross-sectional study design. Level of Evidence 2b Laryngoscope, 2015

Guidance on frameworks for physical resilience, resistance and reserve are underdeveloped. We examined different “physical resilience” characterizations within n=6,538 Atherosclerosis Risk in Communities Study participants (median age: 75 years), followed for 5+ years. Fifteen illustrative clinical, lifestyle and social stressors, each having varying levels of severity, chronicity and relevance, were paired with six functional outcome measure trajectories. Contrasts were made against four fundamental comparator groups (including those without stressors). Particular pairings of stressors and functional measures substantially impacted resilience classifications and related determinants. For example, 5-year recurring robustness (0/5 frailty indicators) was only 12% for participants after Heart Failure (HF), versus 47% with no HF event; relative-risk: RR=0.26 (95%CI: 0.15,0.44). Conversely, recurring robustness was 43% after reporting low social support versus 51% with adequate support; RR=0.87(0.73,1.02). We highlight major components that impacted resilience determinations and outline a broad conceptual framework to help optimize physical resilience assessment and aid future research. Part of a symposium sponsored by Epidemiology of Aging Interest Group.

Physical resilience, generally defined as the ability to recover or resist functional decline following a stressor, holds promise for clinicians to identify patients who are likely to benefit from a planned stressor (such as an elective procedure) or deteriorate after an unplanned stressor (such as heart failure). This symposium will present innovative research approaches that enhance understanding of the constructs of resilience from human and animal models. The symposium will include presentations from leading experts addressing issues in the study of resilience including choices of definitions, study design, comparator groups, and considerations of underlying latent factors. Data from population-based cohort studies and animal models will be presented to inform the discussions. This interdisciplinary symposium will address recommendations for advancing resilience knowledge through elucidating biologic, clinical and environmental influences and optimizing definitions, designs, and analyses. Epidemiology of Aging Interest Group Sponsored Symposium.

Using data from 743 initially well-functioning men and women (49.5%) aged ≥60 in the Baltimore Longitudinal Study of Aging we interrogated the association between physical reserve operationalized as fast 400m walk performance scaled from 0 to 4 and psychological reserve (“will”) operationalized as personal mastery (high versus not) and likelihood of recovery from a decline of ≥2 points in reported walking ability. Of the 35% who declined 1-2 years post study baseline, 54% recovered 1-2 years later and 45% did not. Controlling for age, sex, race and initial walking ability, for each increment in reserve, likelihood of recovery was 43% greater (95% confidence interval (1.10, 1.85); p=.007). This association was most pronounced in women (odds ratio=1.84; 95% CI (1.19, 2.86; p=.006). Personal mastery showed no association with likelihood of recovery. Continuing work will further explore alternative operationalizations of “will”. Part of a symposium sponsored by Epidemiology of Aging Interest Group.

Affiliation of authors Lindsay McElmurray, Dr. Michael Hughes, Dr. Hani Rashed, Dr. William Kennedy, Dr. Gwen Wendelschafer-Crabb, Dr. Xiu Yang, Dr. Mostafa Fraig and Christina Pinkston are updated through this erratum.

Purpose To compare the effectiveness of metastatic tumor response evaluation with computed tomography using computer-assisted versus manual methods. Materials and Methods In this institutional review board–approved, Health Insurance Portability and Accountability Act–compliant retrospective study, 11 readers from 10 different institutions independently categorized tumor response according to three different therapeutic response criteria by using paired baseline and initial post-therapy computed tomography studies from 20 randomly selected patients with metastatic renal cell carcinoma who were treated with sunitinib as part of a completed phase III multi-institutional study. Images were evaluated with a manual tumor response evaluation method (standard of care) and with computer-assisted response evaluation (CARE) that included stepwise guidance, interactive error identification and correction methods, automated tumor metric extraction, calculations, response categorization, and data and image archiving. A crossover design, patient randomization, and 2-week washout period were used to reduce recall bias. Comparative effectiveness metrics included error rate and mean patient evaluation time. Results The standard-of-care method, on average, was associated with one or more errors in 30.5% (6.1 of 20) of patients, whereas CARE had a 0.0% (0.0 of 20) error rate ( P < .001). The most common errors were related to data transfer and arithmetic calculation. In patients with errors, the median number of error types was 1 (range, 1 to 3). Mean patient evaluation time with CARE was twice as fast as the standard-of-care method (6.4 minutes v 13.1 minutes; P < .001). Conclusion CARE reduced errors and time of evaluation, which indicated better overall effectiveness than manual tumor response evaluation methods that are the current standard of care.